Physiology, Islets of Langerhans


Article Author:
Zainab Shahid


Article Editor:
Gurdeep Singh


Editors In Chief:
Chaddie Doerr


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
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Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
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Hussain Sajjad
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Muhammad Hashmi
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Matthew Varacallo
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Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
5/15/2019 8:48:02 PM

Introduction

The islets of Langerhans are clusters of pancreatic cells that were discovered by Dr. Paul Langerhans, a pathologist who also discovered the dendritic Langerhans cells, in 1869.[1] Each islet contains up to a few thousand endocrine cells, and altogether the islets constitute up to 2% of the total pancreatic mass. The cells in the islets include the alpha cells, beta cells, delta cells, epsilon cells, and pancreatic polypeptide (PP) cells, and each cell releases a specific hormone in response to signals.[2]

Cellular

Each islet is made up of a central core of beta cells, surrounded by a mantle of alpha, delta, epsilon, and pancreatic polypeptide cells. Although most islets follow this "mantle-core" pattern, there are variations amongst islets of different sizes. In general, beta cells comprise up to 60% of islet mass, alpha cells comprise up to 30% of islet mass, and delta, epsilon, and pancreatic polypeptide cells make up the remaining 10% of islet mass. The blood supply and innervation for each islet are provided by a neurovascular bundle which penetrates the islet through the central core of beta cells.[3]

Development

The pancreas derives from a dorsal and a ventral bud, both of which arise from the foregut endoderm and fuse during embryogenesis to form the exocrine and endocrine pancreas. The endocrine pancreas begins forming at ten weeks of gestation by single immature epithelial duct cells which multiply and form small islands of cells. These islands are vascularized by 16 weeks of gestation and become encapsulated by connective tissue at this time. The cells eventually differentiate to contain only a single pancreatic hormone each during the second half of gestation.[4]

Function

Each pancreatic endocrine cell releases one specific hormone. The alpha cells release glucagon, a peptide hormone which raises the concentration of glucose and fatty acids in the bloodstream and is the primary catabolic hormone in the body. The beta cells release insulin, a peptide hormone which decreases the concentration of glucose in the blood by stimulating glucose uptake by the liver, skeletal muscle, and adipose tissue via specialized receptors. The delta cells release somatostatin, which inhibits the secretion of both glucagon and insulin. The epsilon cells release ghrelin, a hormone which stimulates appetite, increases fat storage and stimulates the growth hormone release from the pituitary gland. The PP cells release pancreatic polypeptide, which is a satiety hormone that decreases gastric acid secretion, gastric emptying, and upper intestinal motility. All of these cells communicate through extracellular spaces and gap junctions and influence the release of hormones by each other. For example, glucagon release by alpha cells suppresses insulin release by beta cells and vice versa and somatostatin release by delta cells inhibits secretion of both glucagon and insulin by the alpha and beta cells.[5]

Clinical Significance

Dysfunction of the islet cells can lead to pancreatic neuroendocrine tumors. These are rare tumors that account for about 7% of all pancreatic masses. They are generally slow growing and well differentiated and can be either functioning or non-functioning. Between 50 and 75% of pancreatic neuroendocrine tumors are nonfunctioning and therefore are not associated with a hormone-related clinical syndrome.[6] Pancreatic neuroendocrine tumors are not always part of multiple endocrine neoplasia type 1 (MEN1) syndrome.

Multiple endocrine neoplasia type 1 is a rare endocrine tumor syndrome which can cause insulinomas, glucagonomas, and nonfunctioning tumors of the pancreas in addition to tumors of the parathyroid and pituitary glands. It occurs due to an inactivating germline mutation in the MEN1 gene on chromosome 11 in the majority of cases, although 20% of patients with the MEN1 syndrome do not have a mutation in this gene. Pancreatic neuroendocrine tumors can occur in 30 to 75% of patients presenting with this syndrome, and nonfunctioning neuroendocrine tumors are more common than functioning ones. A thorough medical and family history is crucial in making an early diagnosis of MEN1, which can be lifesaving as this syndrome is associated with a high mortality rate.[7]

Nonfunctional Islet Cell Tumor

Non-functioning tumors represent the majority of pancreatic neuroendocrine tumors, and between 60 to 90% of them are malignant. These tumors may release certain substances, such as pancreatic polypeptide and chromogranin A, which are also useful as tumor markers in patients. They do not present clinically with a hormonal syndrome, which can cause a delay in the diagnosis. More than 50% of these tumors are diagnosed incidentally in asymptomatic patients undergoing diagnostic evaluations for other unrelated conditions.[8] Symptoms due to these tumors are due to mass effect and include abdominal pain, weight loss, anorexia, nausea, obstructive jaundice, intra-abdominal hemorrhage, or a palpable mass.[6]

Insulinoma

Insulinomas are the most common functioning tumors and are composed of pancreatic beta cells. They occur in adults between 31 to 63 years old and have a slight female predominance. Morphologically they are small tumors, with up to 80% of them being less than 2 cm, and are distributed equally throughout the head, body, and tail of the pancreas. Although between 5 and 15% of insulinomas can be malignant, the majority of them are benign and amenable to surgical excision.[6]

These tumors secrete high amounts of insulin, a hormone that binds to specific receptors in the liver, adipose tissue, and skeletal muscle and causes glucose uptake in these cells. Therefore, the clinical manifestations of insulinomas are related to hypoglycemia. The neuroglycopenic symptoms include weakness, loss of consciousness, and confusion, and the autonomic symptoms include palpitations, tremors, hunger, and sweating. A feared complication is hypoglycemic coma, which can occur suddenly and lead to brain death. The periods of hypoglycemia occur most commonly after a period of fasting or physical exercise but can also occur without any relationship to meal times or exercise. Fasting hypoglycemia with a glucose level of less than 45 mg/dl with concomitant hyperinsulinemia and elevated level of proinsulin and C-peptide can confirm the diagnosis of insulinoma.[9]

Glucagonoma

Glucagonomas are rare tumors, making up 7% of all functioning pancreatic endocrine tumors, that are composed of pancreatic alpha cells. They occur in adults in their fifth decade of life and have an even distribution between males and females. Morphologically, they are encapsulated and firm, vary in size from 2 to -25cm and occur most commonly in the tail of the pancreas. The majority of these tumors are malignant, and 50 to 80% of patients have metastasis to the liver at initial presentation.[6]

These tumors secrete high amounts of glucagon, a hormone that increases the blood glucose concentration by causing conversion of stored glycogen to glucose within the liver. The clinical manifestations of these tumors are unique. While the most common symptoms are weight loss and necrolytic migratory erythema, patients can also present with cheilitis, diabetes mellitus, anemia, diarrhea, venous thrombosis, and neuropsychiatric symptoms. The rash of necrolytic migratory erythema is often the presenting symptom of an underlying glucagonoma; it begins with erythematous papules and plaques on the face, perineum, and extremities and these lesions later enlarge, coalesce and have a central clearing with peripheral crusting and scaling. It is also often associated with intense pruritis and pain.[10]

Somatostatinoma

Somatostatinomas are very rare tumors of the pancreatic delta cells, occurring in 1 in 40 million people per year. These tumors can arise in both the pancreas and the duodenum, and the vast majority are malignant. They are most commonly found incidentally as they contain immune-reactive granules but cause no functional syndrome. Symptoms due to somatostatinomas are due to mass effect and include abdominal pain, weight loss, and jaundice.[11]


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Physiology, Islets of Langerhans - Questions

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Islets of Langerhans of the pancreas are derived from which germ cell layer?



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A 45-year-old female with no significant past medical history presents to the emergency department due to profound weakness and confusion. Laboratory workup reveals a functioning pancreatic neuroendocrine tumor. Which of the following are the most likely characteristics of her particular tumor?



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A 52-year old male presents to the emergency department after a highway motor vehicle accident. During his laboratory workup, an MRI reveals a mass in the pancreas. Upon further testing, you suspect that the patient has a non-functioning pancreatic neuroendocrine tumor. Which of the following is a clinical manifestation of a nonfunctioning pancreatic neuroendocrine tumor?



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A 60-year-old male presents to the primary care clinic for his yearly checkup. He states that he has not seen his primary care physician for 12 years because he has always been healthy. The patient reveals that he has had vague epigastric abdominal pain for the past month and decided to get a checkup at the insistence of his wife. He also reports intermittent episodes of diarrhea and a 25-pound weight loss over the last three months, which he attributes to stress. He is sent to the local hospital for abdominal imaging, which reveals a mass in the head of the pancreas and multiple gallstones. Further testing reveals an HbA1c level of 8.5%. Which of the following cells most likely constitute his pancreatic tumor?



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A 23-year-old female with no significant past medical history presents to the emergency department with weakness and tremors. She states that she has had intermittent periods with similar symptoms over the past two months. Laboratory workup reveals elevated levels of insulin, proinsulin, and c-peptide and a glucose level of 40 mg/dl. Her family history is significant for parathyroid tumors and insulinomas. Which of the following is the most likely cause of her symptoms?



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A 56-year-old male presents to the emergency department due to weight loss and rash. Laboratory workup yields the diagnosis of a glucagonoma. What percentage of one pancreatic islet is composed of the cells that normally make up the involved tissue?



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Physiology, Islets of Langerhans - References

References

Jolles S, Paul Langerhans. Journal of clinical pathology. 2002 Apr;     [PubMed]
Ionescu-Tirgoviste C,Gagniuc PA,Gubceac E,Mardare L,Popescu I,Dima S,Militaru M, A 3D map of the islet routes throughout the healthy human pancreas. Scientific reports. 2015 Sep 29;     [PubMed]
Fowden AL,Hill DJ, Intra-uterine programming of the endocrine pancreas. British medical bulletin. 2001;     [PubMed]
Da Silva Xavier G, The Cells of the Islets of Langerhans. Journal of clinical medicine. 2018 Mar 12;     [PubMed]
Grozinsky-Glasberg S,Mazeh H,Gross DJ, Clinical features of pancreatic neuroendocrine tumors. Journal of hepato-biliary-pancreatic sciences. 2015 Aug;     [PubMed]
Singh G,Jialal I, Multiple Endocrine Neoplasia Type 1 (MEN I, Wermer Syndrome) 2019 Jan;     [PubMed]
Gorelik M,Ahmad M,Grossman D,Grossman M,Cooperman AM, Nonfunctioning Incidental Pancreatic Neuroendocrine Tumors: Who, When, and How to Treat? The Surgical clinics of North America. 2018 Feb;     [PubMed]
Okabayashi T,Shima Y,Sumiyoshi T,Kozuki A,Ito S,Ogawa Y,Kobayashi M,Hanazaki K, Diagnosis and management of insulinoma. World journal of gastroenterology. 2013 Feb 14;     [PubMed]
Foss MG,Ferrer-Bruker SJ, Necrolytic Migratory Erythema 2019 Jan;     [PubMed]
Vinik A,Pacak K,Feliberti E,Perry RR, Somatostatinoma 2000;     [PubMed]
Bonner-Weir S,Sullivan BA,Weir GC, Human Islet Morphology Revisited: Human and Rodent Islets Are Not So Different After All. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. 2015 Aug     [PubMed]

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